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Impaired mitochondrial biogenesis is a common feature to myocardial hypertrophy and end-stage ischemic heart failure.

ABSTRACT: Mitochondrial (mt) DNA depletion and oxidative mtDNA damage have been implicated in the process of pathological cardiac remodeling. Whether these features are present in the early phase of maladaptive cardiac remodeling, that is, during compensated cardiac hypertrophy, is still unknown. We compared the morphologic and molecular features of mt biogenesis and markers of oxidative stress in human heart from adult subjects with compensated hypertrophic cardiomyopathy and heart failure. We have shown that mtDNA depletion is a constant feature of both conditions. A quantitative loss of mtDNA content was associated with significant down-regulation of selected modulators of mt biogenesis and decreased expression of proteins involved in mtDNA maintenance. Interestingly, mtDNA depletion characterized also the end-stage phase of cardiomyopathies due to a primary mtDNA defect. Oxidative stress damage was detected only in failing myocardium.

SUBMITTER: Pisano A

PROVIDER: S-EPMC4758811 | biostudies-other | 2016 Mar-Apr

REPOSITORIES: biostudies-other

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Impaired mitochondrial biogenesis is a common feature to myocardial hypertrophy and end-stage ischemic heart failure.

Pisano Annalinda A Cerbelli Bruna B Perli Elena E Pelullo Maria M Bargelli Valentina V Preziuso Carmela C Mancini Massimiliano M He Langping L Bates Matthew G D MG Lucena Joaquin R JR Della Monica Paola Lilla PL Familiari Giuseppe G Petrozza Vincenzo V Nediani Chiara C Taylor Robert W RW d'Amati Giulia G Giordano Carla C

Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology 20150930 2

Mitochondrial (mt) DNA depletion and oxidative mtDNA damage have been implicated in the process of pathological cardiac remodeling. Whether these features are present in the early phase of maladaptive cardiac remodeling, that is, during compensated cardiac hypertrophy, is still unknown. We compared the morphologic and molecular features of mt biogenesis and markers of oxidative stress in human heart from adult subjects with compensated hypertrophic cardiomyopathy and heart failure. We have shown ...[more]

PMID: 26764143

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Project description:BackgroundThe aims of our study were (1) to assess the right ventricular (RV) myocardial mechanics by two-dimensional (2D) and three-dimensional (3D) speckle-tracking echocardiography (STE) in patients with an ischemic or non-ischemic etiology of end-stage heart failure (HF) and (2) to explore which RV index evaluated by 2D- and 3D-STE was the most powerful indicator for identifying the ischemic and non-ischemic etiologies of end-stage HF.MethodsA total of 96 patients with left ventricular ejection fraction (LVEF) < 30% were enrolled in our study: 42 patients (mean age, 52 ± 10 years; 9.5% female) with ischemic cardiomyopathy and 54 patients (mean age, 46 ± 14 years; 16.7% female) with non-ischemic cardiomyopathy. A total of 45 healthy subjects (mean age, 46 ± 13 years; 24.4% female) served as controls. The longitudinal strain of the RV free wall (RVFWLS) was determined by both 2D- and 3D-STE.ResultsCompared to controls, patients with an ischemic or non-ischemic etiology of end-stage HF had lower 2D-RVFWLS, 3D-RVFWLS and RV ejection fraction (RVEF) values (P < 0.05). Patients with non-ischemic cardiomyopathies (NICMs) had significantly lower 3D-RVFWLS and RVEF values than in those with ischemic cardiomyopathies (ICMs), whereas 2D-RVFWLS and conventional RV function parameters did not differ between the two subgroups. RVEF was highly related to 3D-RVFWLS (r = 0.72, P < 0.001), modestly related to 2D-RVFWLS (r = 0.51, P < 0.001), and weakly related to conventional RV function indices (r = -0.26 to 0.46, P < 0.05). Receiver operating characteristic curve analysis revealed that the optimal 3D-RVFWLS cut-off value to distinguish NICM from ICM patients was -14.78% (area under the curve: 0.73, P < 0.001), while 2D-RVFWLS and conventional RV echocardiographic parameters did not.ConclusionOur study demonstrated the superiority of 3D-RVFWLS over 2D-RVFWLS and conventional RV function indices in identifying the ischemic and non-ischemic etiologies of end-stage HF. These findings support the idea that 3D-RVFWLS may be a promising non-invasive imaging marker for distinguishing NICM from ICM.

Project description:BACKGROUND:Myocardial flow reserve (MFR, stress/rest myocardial blood flow) is a strong marker of myocardial vasomotor function. MFR is a predictor of adverse cardiac events in patients with non-ischemic systolic heart failure and previous studies using different methods have found association between myocardial blood flow and left ventricular dilatation. The aim of this study was to investigate whether there is an association between increasing end-systolic- and end-diastolic volumes (ESV and EDV) and MFR in these patients measured with Rubidium-82 positron emission tomography computed tomography (82Rb-PET/CT) as a quantitative myocardial perfusion gold-standard. METHODS:We scanned 151 patients with non-ischemic heart failure with initial left ventricular ejection fraction ?35% with 82Rb-PET/CT at rest and adenosine-induced stress to obtain MFR and volumes. To account for differences in body surface area (BSA), we used indexed ESV (ESVI): ESV/BSA (ml/m2) and EDV (EDVI). We identified factors associated with MFR using multiple regression analyses. RESULTS:Median age was 62?years (55-69?years) and 31% were women. Mean MFR was 2.38 (2.24-2.52). MFR decreased significantly with both increasing ESVI (estimate -?3.7%/10?ml/m2; 95% confidence interval [CI] -5.6 to -?1.8; P?<?0.001) and increasing EDVI (estimate -?3.5%/10?ml/m2; 95% CI -5.3 to -?1.6; P?<?0.001). Results remained significant after multivariable adjustment. Additionally, coronary vascular resistance during stress increased significantly with increasing ESVI (estimate: 3.1?mmHg/(ml/g/min) per (10?ml/m2); 95% CI 2.0 to 4.3; r?=?0.41; P?<?0.0001) and increasing EDVI (estimate: 2.7?mmHg/(ml/g/min) per (10?ml/m2); 95% CI 1.6 to 3.8; r?=?0.37; P?<?0.0001). CONCLUSIONS:Impaired MFR assessed by 82Rb-PET/CT was significantly associated with linear increases in ESVI and EDVI in patients with non-ischemic systolic heart failure. Our findings support that impaired microvascular function may play a role in heart failure development. Clinical trials investigating MFR with regard to treatment responses may elucidate the clinical use of MFR in patients with non-ischemic systolic heart failure. TRIAL REGISTRATION:Sub study of the randomized clinical trial: A DANish randomized, controlled, multicenter study to assess the efficacy of Implantable cardioverter defibrillator in patients with non-ischemic Systolic Heart failure on mortality (DANISH), ClinicalTrials.gov Identifier: NCT00541268 .

Dataset Information

Impaired mitochondrial biogenesis is a common feature to myocardial hypertrophy and end-stage ischemic heart failure.

Publications

Impaired mitochondrial biogenesis is a common feature to myocardial hypertrophy and end-stage ischemic heart failure.

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